The present invention relates to hydroxyalkyl substituted purines and pyrimidines having a fused cyclopropane ring in the hydroxyalkyl side chain and the heterocyclic isosteres of said purines and pyrimidines. These compounds have antiviral activity. The compounds are particularly effective against herpes viruses, e.g. herpes simplex virus. The present invention also relates to processes for preparing such compounds.
The compounds of the invention may be represented by the formula ##STR1## and the pharmaceutically acceptable salts thereof wherein Y is a purin-9-yl or a pyrimidin-1-yl or a hetercyclic isostere of a purin-9-yl or a pyrimidin-1-yl group; R.sup.1 is selected from hydrogen and alkyl of 1 to 4 carbon atoms; R.sup.2 is selected from hydrogen, alkyl of 1 to 4 carbon atoms and --CH.sub.2 OH; and Z is &gt;CH.sub.2 or &gt;O.
Preferably, Y is guanine, a guanine isostere, adenine, cytosine, uracil, thymine or 2-amino-6-chloropurine.
Most preferably, Y is guanine.
An isostere is a molecule which is isosteric with another molecule; that is, has a similarity of structure and a resulting similarity of properties exhibited by the molecules. The molecules may contain different atoms and not necessarily the same number of atoms, but possess the same total or valence elections in the same arrangement, viz. carbon monoxide (C.dbd.O) and atmospheric nitrogen (N.dbd.N), or cyanide ion (--C.tbd.N) and acetylide ion (--C.tbd.CH).
Other heterocyclic systems isosteric with purine include 7-deazapurine (e.g. pyrrolo[2,3-d]pyrimidine), 8-azapurine (e.q. v-triazolo[4,5-d]pyrimidine), 3-deazapurine (e.g. imidazo[4,5-C]pyridine), and 1-deaza-5-azapurine (e.g. s-triazolo-[2,3-a]pyrimidine etc. Some heterocyclic systems isosteric with oxopyrimidines include 3-deazauracil (e.g. 2,4-dihydroxypyridine), 6-azauracil (e.g. 3,5-dihydroxy-1,2,4-triazine), and 5-azacytosine (2-amino-4-hydroxy-1,3,5-triazine).
The following are representative compounds of the present invention:
9-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]guanine PA0 9-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]guanine PA0 9-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]adenine PA0 9-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]adenine PA0 9-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]guanine PA0 9-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]adenine PA0 9-[(E)-2,3-Epoxy-4-hydroxybutyl]guanine PA0 9-[(Z)-2,3-Epoxy-4-hydroxybutyl]guanine PA0 9-[(E)-2,3-Epoxy-4-hydroxybutyl]adenine PA0 9-[(Z)-2,3-Epoxy-4-hydroxybutyl]adenine PA0 9-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]guanine PA0 9-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]guanine PA0 9-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]adenine PA0 9-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]adenine PA0 9-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]-2-amino-6-chloropurine PA0 9-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]-2-amino-6-chloropurine PA0 9-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]-2-amino-6-chloropurine PA0 9-[(E)-2,3-Epoxy-4-hydroxybutyl]-2-amino-6-chloropurine PA0 9-[(Z)-2,3-Epoxy-4-hydroxybutyl]-2-amino-6-chloropurine PA0 9-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]-2-amino-6-chloropurin e PA0 9-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]-2-amino-6-chloropurin e PA0 1-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[(E)-2,3-Epoxy-4-hydroxybutyl]thymine PA0 1-[(Z)-2,3-Epoxy-4-hydroxybutyl]thymine PA0 1-[(E)-2,3-Epoxy-4-hydroxybutyl]uracil PA0 1-[(Z)-2,3-Epoxy-4-hydroxybutyl]uracil PA0 1-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]thymine PA0 1-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]thymine PA0 1-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]uracil PA0 1-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]uracil PA0 1-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(2,2)-Bis(hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(E)-2,3-Epoxy-4-hydroxybutyl]cytosine PA0 1-[(Z)-2,3-Epoxy-4-hydroxybutyl]cytosine PA0 1-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]cytosine PA0 1-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]cytosine. PA0 9-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]guanine PA0 9-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]adenine PA0 9-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]adenine PA0 9-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]guanine.
The following compounds are preferred:
The compounds of the present invention may be prepared by various methods. The following three schemes illustrate these methods: ##STR2##
According to one method (Scheme I), which is similar to that of Noell et al., J. Med. Pharm. Chem., 5, 558 (1962), 6-chloroisocytosine of Formula I, [2-amino-6-chloro-4(3H)-pyrimidinone]is reacted with an excess amount of the appropriate amino alcohol of Formula II. The reaction is conducted at elevated temperature in a suitable high boiling, polar solvent, preferably 2-ethoxyethanol, at reflux. Preferably, about three equivalents of the compound of Formula II are used per equivalent of the compound of Formula I. Alternatively, a lesser amount of the compound of Formula II, preferably from about 1.5 to 2 equivalents, may be used if a compatible base is added to the reaction mixture to scavenge the HCl liberated during the reaction. Compatible bases include high-boiling tertiary aliphatic amines such as 1,4-diazabicyclo[2.2.2]-octane (DABCO). The reaction is run for from about 1 to about 18 hours, preferably for from about 1 to about 3 hours.
The resulting 6-(hydroxyalkylamino)isocytosine of Formula III need not be isolated but may be treated directly with sodium nitrite in aqueous acetic acid at about room temperature to give the 5-nitroso derivative of Formula IV which is readily isolated. Reduction of the nitroso group of the compound of formula IV gives the compound of formula V. The nitroso group of the compound of Formula IV is reduced under conditions such that the resulting amino group is formylated in situ (at least partial formylation of the terminal hydroxyl group of the side chain also normally occurs under these conditions). The reduction and formylation may be carried out by a variety of methods such as, for example, sodium dithionite in the presence of formic acid, or zinc dust in formic acid, or catalytic hydrogenation (e.g., using 10% palladium on carbon) in formic acid. The compound of Formula V is usually reacted directly in the next step without purification. Cyclization of the 5-formamido-6-(substituted-alkylamino)isocytosine to a guanine derivative may be accomplished by various means such as, for example, heating with formamide in the presence of formic acid at elevated temperature of from 150.degree. to about 190.degree. (bath temperature) for from about 2 to about 4 hours or by other methods described in the literature, for example, Lister, "Fused Pyrimidines, Part II: Purines", editor, D. J. Brown, John Wiley and Sons, Inc., 1971, Chapter II. Final treatment with a warm aqueous base such as, e.g., methylamine or sodium hydroxide solution, serves to remove any residual formyl groups and allows the isolation of the compound of Formula VI.
Similarly, isosteres of compounds of Formula VI may be prepared from intermediates having the Formula III or IV. For example, cyclization of III with chloroacetaldehyde in sodium acetate buffer and deprotection produces the corresponding 7-deazapurine analogue of the compound of Formula VI. Similarly, chemical or catalytic reduction of IV produces the 5-amino derivative which may be cyclized to the 8-azapurine isostere of the compound of Formula VI after appropriate deprotection. Thus, an important embodiment of the invention relates to compounds of the Formulae III, IV and V and the 5-amino analogues thereof.
The 9-substituted guanines of Formula VI may also be prepared (Scheme II) by alkylation of a preformed purine derivative of Formula XII (e.g., 2,6-dichloropurine, 2-amino-6-chloropurine or 2-amino-6-benzyloxypurine) with a compound of Formula XIII, wherein X is a leaving group such as bromo, chloro, iodo, tosyl, mesyl and the like, and Q is a protecting group removable by hydrolysis such as, for example, benzoyl or acetyl, or by hydrogenolysis such as, for example, benzyl. The alkylation is normally carried out in the presence of a base such as, for example, potassium carbonate, in a suitable solvent such as, for example, dimethylformamide or dimethylsulfoxide. The 9-alkylated product of Formula XIV may be separated from any isomers (e.g., the 7-alkylated isomer) chromatographically or by other means. Transformation of the substituents Z and W to give the guanine and removal of the protecting group Q may be accomplished by standard methods known to those skilled in the art.
Scheme III illustrates the preparation of 9-[(Z)-2-(hydroxymethyl)cyclopropylmethyl]adenine. The chloromethylcyclopropane XVII may also be used to alkylate other purines (e.g. 6-chloropurine, which may be converted to an adenine using known methods, or 2,6-dichloropurine or 2-amino-6-chloropurine, which may be converted to a guanine using known methods) or to alkylate pyrimidines or other isosteric heterocyclic systems. The following schemes IV and V illustrate alkylation of pyrimidines: ##STR3##
The pyrimidines, thymine (XX) and cytosine (XXIII) are reacted with the chloromethylcyclopropane XVII (Schemes IV and V, respectively) in the presence of sodium iodide and a base such as potassium carbonate in a polar solvent such as dimethyl sulfoxide or dimethyl formamide, preferably at a temperature of about 70 to 90.degree. C. The alkylated pyrimidines may be purified by chromatography. The benzoyl protecting group may then be removed by standard conditions such as aqueous methylamine, methanolic ammonia, or catalytic sodium methoxide in methanol.
The synthetic schemes II-V are readily amenable to the synthesis of isosteric purine and oxypyrimidine compounds. This may be accomplished by simply substituting the appropriately preformed isosteric heterocycle for the purine or oxypyrimidine which undergoes the alkylation reaction, i.e., Compound XII in Scheme II; adenine in Step 3, Scheme III; Compound XX in Scheme IV; and Compound XXIII in Scheme V.
Pharmaceutically acceptable salts are prepared by recrystallization of the desired adenine guanine, 2-amino-6-chloropurine, cytosine, uracil or thymine derivative as the free base or as the acetate or hydrochloride from the aqueous dilute acid of choice. Acid addition salts of adenine derivatives are more stable than the corresponding salts of guanine derivatives. Alkali metal salts of guanine, thymine and uracil derivatives can be made by standard techniques, for example, by dissolving such derivative in water containing one equivalent of an alkali metal hydroxide, followed by evaporation to dryness.
In another aspect of the invention there is provided a pharmaceutical composition or preparation comprising a compound of the formula ##STR4## wherein Y, Z, R.sup.1 and R.sup.2 are as hereinbefore defined; or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor. In a particular aspect the pharmaceutical composition comprises a compound of the present invention in effective unit dosage form.
As used herein the term "effective unit dosage" or "effective unit dose" is denoted to mean a predetermined antiviral amount sufficient to be effective against the viral organisms in vivo. Pharmaceutically acceptable carriers are materials useful for the purpose of administering the medicament, and may be solid, liquid or gaseous materials, which are otherwise inert and medically acceptable and are compatible with the active ingredients.
These pharmaceutical compositions may be given parenterally, orally, used as a suppository or pessary, applied topically as an ointment, cream, aerosol, powder, or given as eye or nose drops, etc., depending on whether the preparation is used to treat internal or external viral infections.
For internal infections the compositions are administered orally or parenterally at dose levels of about 0.1 to 250 mg per kg, preferably 1.0 to 50 mg per kg of mammal body weight, and are used in man in a unit dosage form, administered, e.g. a few times daily, in the amount of 1 to 250 mg per unit dose.
For oral administration, fine powders or granules may contain diluting, dispersing and/or surface active agents, and may be presented in a draught, in water or in a syrup; in capsules or sachets in the dry state or in a non-aqueous solution or suspension, wherein suspending agents may be included; in tablets, wherein binders and lubricants may be included; or in a suspension in water or a syrup. Where desirable or necessary, flavoring, preserving, suspending, thickening or emulsifying agents may be included. Tablets and granules are preferred, and these may be coated.
For parenteral administration or for administration as drops, as for eye infections, the compounds may be presented in aqueous solution in a concentration of from about 0.1 to 10%, more preferably 0.1 to 7%, most preferably 0.2% w/v. The solution may contain antioxidants, buffers, etc.
Alternatively, for infections of the eye, or other external tissues, e.g. mouth and skin, the compositions are preferably applied to the infected part of the body of the patient as a topical ointment or cream. The compounds may be presented in an ointment, for instance, with a water soluble ointment base, or in a cream, for instance with an oil in water cream base, in a concentration of from about 0.1 to 10%, preferably 0.1 to 7%, most preferably 1% w/v.